Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

• Main Authors: Chahrour, Maria H. (Author), Yu, Timothy W. (Author), Lim, Elaine T. (Author), Ataman, Bulent (Author), Coulter, Michael E. (Author), Hill, R. Sean (Author), Stevens, Christine R. (Author), Schubert, Christian R. (Contributor), Greenberg, Michael E. (Author), Gabriel, Stacey B. (Author), Walsh, Christopher A. (Author)
• Other Authors: Massachusetts Institute of Technology. Research Laboratory of Electronics (Contributor)
• Format: Article
• Language: English
• Published: Public Library of Science, 2012-07-23T18:55:57Z.
• Subjects: Article
• Online Access: Get fulltext

 Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.